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EP0785794B1 - Zubereitungen von 1,5-benzodiazepinderivaten mit cck-antagonistischen oder agonistischer wirkung mit enterischem überzug - Google Patents

Zubereitungen von 1,5-benzodiazepinderivaten mit cck-antagonistischen oder agonistischer wirkung mit enterischem überzug Download PDF

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Publication number
EP0785794B1
EP0785794B1 EP95935725A EP95935725A EP0785794B1 EP 0785794 B1 EP0785794 B1 EP 0785794B1 EP 95935725 A EP95935725 A EP 95935725A EP 95935725 A EP95935725 A EP 95935725A EP 0785794 B1 EP0785794 B1 EP 0785794B1
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alkyl
phenyl
group
hydroxy
hydrogen
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EP0785794A1 (de
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Elizabeth Ellen Sugg
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SmithKline Beecham Corp
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Glaxo Wellcome Inc
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A61K31/551—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having two nitrogen atoms, e.g. dilazep
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
    • A61K38/05—Dipeptides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/04—Anorexiants; Antiobesity agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
    • A61K9/2806—Coating materials
    • A61K9/2833—Organic macromolecular compounds
    • A61K9/286—Polysaccharides, e.g. gums; Cyclodextrin
    • A61K9/2866—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose

Definitions

  • This invention relates to pharmaceutical compositions containing novel 1,5-benzodiazepine derivatives which exhibit agonist activity for CCK-A receptors thereby enabling them to modulate the hormones gastrin and cholecystokinin (CCK) in mammals.
  • CCK cholecystokinin
  • Cholecystokinins (CCK) and gastrin are structurally related peptides which exist in gastrointestinal tissue and in the central nervous system. Cholecystokinins include CCK-33, a neuropeptide of thirty-three amino acids in its originally isolated form, its carboxyl terminal octapeptide, CCK-8 (also a naturally occurring neuropeptide), and 39- and 12-amino acid forms. Gastrin occurs in 34-, 17- and 14- amino acid forms, with the minimum active sequence being the C-terminal tetrapeptide, Trp-Met-Asp-Phe-NH 2 (CCK-4) which is the common structural element shared by both CCK and gastrin.
  • CCK-33 a neuropeptide of thirty-three amino acids in its originally isolated form, its carboxyl terminal octapeptide, CCK-8 (also a naturally occurring neuropeptide), and 39- and 12-amino acid forms.
  • Gastrin occurs in 34-, 17- and 14- amino acid
  • CCK and gastrin are gastrointestinal hormones and neurotransmitters in the neural and peripheral systems and perform their respective biological roles by binding to particular receptors located at various sites throughout the body.
  • the CCK-A receptor commonly referred to as the "peripheral-type" receptor, is primarily found in the pancreas, gallbladder, ileum, pyloric sphincter and on vagal afferent nerve fibers.
  • Type-A CCK receptors are also found in the brain in discrete regions and serve to provide a number of CNS effects. Due to the ability of CCK-8 and Type-A CCK-selective agonists to suppress food intake in several animal species, considerable interest has been generated toward the development of new substances which function as Type-A receptor-selective CCK agonists in order to serve as anorectic agents.
  • CCK-B or gastrin receptors are found in peripheral neurons, gastrointestinal smooth muscle and gastrointestinal mucosa, most notably in parietal cells, ECL cells, D cells and chief cells. CCK-B receptors also predominate in the brain and have been implicated in the regulation of anxiety, arousal and the action of neuroleptic agents.
  • the present invention thus provides a pharmaceutical formulation in solid dosage form for oral administration which comprises a compound of the general Formula (I) and physiologically salts and solvate thereof wherein:
  • the formulation according to the invention is in the form of a tablet coated with a conventional enteric coating.
  • the formulation according to the invention may be presented in the form of a capsule the shell of which is made from enteric material or is coated with an enteric material.
  • enteric coating or material refers to a coating or material that will pass through the stomach essentially intact but will rapidly disintegrate in the small intestine to release the active drug substance.
  • the tablets and capsules for oral administration may contain conventional excipients such as binding agents, (for example, syrup, acacia, gelatin, sorbitol, tragacanth, mucilage of starch or polyvinylpyrrolidone), fillers (for example, lactose, sugar, microcrystalline cellulose, maize-starch, calcium phosphate or sorbitol), lubricants (for example, magnesium stearate, stearic acid, talc polyethylene glycol or silica), disintegrants (for example, potato starch or sodium starch glycollate) or wetting agents, such as sodium lauryl sulphate.
  • binding agents for example, syrup, acacia, gelatin, sorbitol, tragacanth, mucilage of starch or polyvinylpyrrolidone
  • fillers for example, lactose, sugar, microcrystalline cellulose, maize-starch, calcium phosphate or sorbitol
  • lubricants for example
  • Suitable enteric coatings for use in the invention will be these coatings known to those skilled in the art.
  • Such coatings include cellulose acetate phthalate, polyvinyl acetate phthalate, shellac, styrene maleic acid copolymers, methyacrylic acid copolymers and hydroxypropyl methyl cellulose phthalate.
  • the said coatings may also contain a plasticizer and or a dye.
  • examples of such a group include those wherein R 6 is hydrogen or more particularly methyl, R 7 is hydrogen, hydroxyl, methoxy, or fluorine, and n is 1.
  • examples of such a group include those wherein R 6 is hydrogen or more particularly methyl, R 7 is hydrogen, hydroxyl, methoxy, or fluorine, and n is 1.
  • R 1 represents the group NR 4 R 5
  • suitable groups include those wherein R 4 represent C 3-6 alkyl, such as propyl or isopropyl, cyclohexyl or phenyl and R 5 represents C 3-6 alkyl, benzyl or phenyl optionally substituted in the para- position by hydroxy, dimethylamino methoxy, trifluoromethyl, fluorine, pyrrolidino or morpholino.
  • R 1 groups include those wherein R 4 is propyl and, more particularly, isopropyl and R 5 represents phenyl or phenyl substituted in the para-position by groups selected from hydroxy, methoxy dimethylamino, fluorine, or morpholino.
  • R 1 groups include those wherein R 1 is the group of Formula (II) wherein R 6 is methyl, n is 1 and R 7 is hydrogen, hydroxy, fluorine or methoxy or R 1 is the group NR 4 R 5 wherein R 4 is propyl or isopropyl and R 5 is phenyl optionally substituted in the para position by a group selected from hydroxy, methoxy, fluoro, dimethylamino, pyrrolidino or morpholino.
  • R 1 is the group of Formula (II) wherein R 6 is methyl, n is 1 and R 7 is hydrogen, hydroxy, fluorine or methoxy or R 1 is the group NR 4 R 5 wherein R 4 is propyl or isopropyl and R 5 is phenyl optionally substituted in the para position by a group selected from hydroxy, methoxy, fluoro, dimethylamino, pyrrolidino or morpholino.
  • R 9 is conveniently a group selected from hydrogen, methyl, methoxy, hydroxy, nitro or amino and, where appropriate, the optional substituent on nitrogen, (R 8 ), is -CH 2 CO 2 H.
  • R 2 is an optionally substituted phenyl group, this is conveniently phenyl or phenyl substituted by one or two groups, which may be the same or different and selected from chlorine, fluorine, amino, hydroxy or carboxyl.
  • R 11 is conveniently phenyl (optionally substituted by fluoro, hydroxy, amino, dimethylamino, trifluoromethylsulphonylamino, C 1-4 alkoxycarbonyl, carboxy, 1 H-tetrazol-5-yl, acetylamino or OR 12 wherein R 12 represents hydrogen, methyl, benzyl, CH 2 CO 2 H, CH 2 CONH 2 , CH 2 CONHCH 3 , CH 2 CON(CH 3 ) 2 ) or a 7-indazolyl group wherein the N-1 substituent, (R 10 ), is hydrogen.
  • R 11 is a mono substituted phenyl group
  • the substituted is conveniently in the meta- position.
  • R 2 groups examples include indole, benzofuran, thiophene, benzothiophene, indoline, quinoline, 4-oxobenzopyran, an optionally substituted phenyl group or the group NHR 11 .
  • R 2 is selected from the group indole, indoline or benzofuran, an optionally substituted phenyl group or the group NHR 11 . More particularly, R 2 represents an indole, an optionally substituted phenyl or NHR 11 .
  • R 3 represents C 1-6 alkyl
  • suitable groups include methyl, ethyl, propyl, isopropyl, butyl, t-butyl or isoamyl.
  • R 3 represents C 3-6 cycloalkyl
  • suitable groups include cyclopropyl, cyclopentyl or cyclohexyl.
  • R 3 represents phenyl, mono or disubstituted by independently with halogen
  • suitable groups include those wherein the halogen substituent is fluorine e.g., 2-fluorophenyl or 4 fluorophenyl.
  • R 3 groups include hydrogen, methyl, cyclohexyl, 2-fluorophenyl or phenyl, and more particularly, phenyl.
  • R 1 represents the group of Formula (II) wherein R 6 is methyl, n is 1 and R 7 is hydrogen, fluorine, hydroxy or methoxy, or more particularly NR 4 R 5 wherein R 4 is propyl or isopropyl and R 5 is phenyl optionally substituted in the para position by a group selected from hydroxy, methoxy, fluoro, dimethylamino or morpholino;
  • R 2 represents phenyl (optionally substituted independently by one or two groups selected from chlorine, fluorine, hydroxy, amine or carboxy), NHR 11 wherein R 11 represents phenyl (optionally substituted by amino, dimethylamino, trifluoromethyl- sulphonylamino, carboxy, 1H-tetrazol-5-yl, acetylamino or OR 12 wherein R 12 represents hydrogen, methyl, benzyl, CH 2 CO 2 H, CH 2 CONH 2 ,
  • a particularly interesting class of compounds for use in the formulation according to the present invention because they exhibit a very high and selective affinity for the CCK-A receptor as well as exceptional efficacy are those wherein R 2 is an indole group.
  • R 2 is an indole group.
  • a preferred group of compounds within this class are those wherein the indole group is substituted on the nitrogen atom by the group -CH 2 CO 2 H or, more preferably, the nitrogen atom is unsubstituted, and benzo ring of the indole group is optionally substituted by a group selected from chlorine, methyl, methoxy, nitro, hydroxy or amino.
  • a particularly preferred compound for use in the formulation according to the invention is : 1 H-lndole-2-carboxylic acid ⁇ 1-[Isopropyl-(4-methoxyphenyl)carbamoylmethyl]-2,4-dioxo-5-phenyl-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-3-yl ⁇ amide and enantiomers thereof.
  • alkyl is generally intended to mean both straight chain and branched chain aliphatic isomers of the corresponding alkyl.
  • C 1-6 alkyl is intended to include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tertbutyl, n-pentyl, etc.
  • cycloalkyl as provided herein, is intended to mean all alicyclic isomers of the corresponding alkyl.
  • C 3-6 alkyl as provided herein, is intended to include such groups as cyclopropyl, cyclopentyl and cyclohexyl.
  • halogen is intended to mean F, Cl, Br or I.
  • tetrazole as a group or part of a group refers to the (1 H)-tetrazol-5-yl grouping and tautomers thereof.
  • the present invention includes all possible stereoisomers and geometric isomers of Formula (I) and includes not only racemic compounds but also the optically active isomers as well.
  • a compound of Formula (I) When a compound of Formula (I) is desired as a single enantiomer, it may be obtained either by resolution of the final product or by stereospecific synthesis from either isomerically pure starting material or any convenient intermediate. Resolution of the final product, an intermediate or a starting material may be effected by any suitable method known in the art. See, for example, Stereochemistry of Carbon Compounds by E. L. Eliel (Mcgraw Hill, 1962) and Tables of Resolving Agents by S. H. Wilen. Additionally, in situations where tautomers of the compounds of Formula (I) are possible, the present invention is intended to include all tautomeric forms of the compounds.
  • the compounds of the present invention may also be utilized in the form of a pharmaceutically acceptable salt or solvate thereof.
  • physiologically acceptable salts of the compounds of Formula (I) include conventional salts formed from pharmaceutically acceptable inorganic or organic acids as well as quaternary ammonium acid addition salts.
  • Suitable salts include hydrochloric, hydrobromic, sulphuric, phosphoric, nitric, perchloric, fumaric, acetic, propionic, succinic, glycolic, formic, lactic, maleic, tartaric, citric, pamoic, malonic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic, fumaric, toluenesulphonic, methanesulphonic, naphthalene-2-sulphonic, benzenesulphonic and the like.
  • Other acids such as oxalic, while not in themselves pharmaceutically acceptable, may be useful in the preparation of salts useful as intermediates in obtaining the compounds of the invention and their pharmaceutically acceptable salts.
  • References hereinafter to a compound for use in the invention include both compounds of Formula (I) and their pharmaceutically acceptable salts and solvates.
  • the compounds of formula (I) exhibit CCK-A agonist activity and can be considered full or partial cholecystokinin agonists in that they bind to CCK-A receptors and either fully or partially stimulate gallbladder contraction and/or reduce feeding in animal paradigms.
  • the compounds of formula (I) are useful anorectic agents advantageous in the treatment of obesity as well as related pathologies, such as diabetes or hypertension. Moreover, the compounds disclosed herein provide for new approaches for inducing satiety, providing for appetite regulation and modifying food intake in mammals, especially humans, to regulate appetite, treat obesity and maintain weight loss.
  • certain compounds of formula (I) may also exhibit some antagonist activity at particular site-specific CCK-B and gastrin receptors as demonstrated by their inhibition of CCK-4 stimulated contraction of isolated guinea-pig ileum longitudinal muscle-myenteric plexus and pentagastrin-stimulated acid secretion in rat isolated gastric mucosa using the procedures described by M. Patel and C. F. Spraggs in Br. J. Pharmac., (1992), 106, 275-282 and by J. J. Reeves and R. Stables in Br. J. Pharmac., (1985), 86, 677-684.
  • the relative affinities of compounds of formula (I) for the CCK-A and CCK-B receptors may be determined using known conventional procedures such as described by Fornos et al J. Pharmacol Exp. Ther., 1992 261 , 1056-1063.
  • compouds of formula (I) to inhibit gastric acid secretion such as pentagastrin stimulated acid secretion may be determined in the conscrious gastric fistula rat using methods described by Hedges and Parsons Journal of Physiology 1977, 267 191-194.
  • a method for the treatment of a mammal including man, in particular in the treatment conditions where modification of the effects of CCK and/or gastrin is of therapeutic benefit, the method comprising administering to the patient an enterically coated tablet or capsule containing a therapeutically effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt or solvate thereof.
  • treatment extends to prophylaxis as well as the treatment of established diseases or symptoms.
  • amount of a compound of the invention required for use in treatment will vary with the nature of the condition being treated and the age and the condition of the patient and will be ultimately at the discretion of the attendant physician or veterinarian. In general, however, doses employed for adult human treatment will typically be in the range of 0.02 - 5000 mg per day, e.g., 1-1500 mg per day. The desired dose may conveniently be presented in a single dose or as divided doses administered at appropriate intervals, for example as two, three, four or more sub-doses per day.
  • Tablet Active Ingredient 50 mg Lactose anhydrous USP 163 mg Microcrystalline Cellulose NF 69 mg Pregelatinized starch Ph. Eur. 15 mg Magnesium stearate USP 3 mg Compression weight 300 mg
  • the active ingredient, microcrystalline cellulose, lactose and pregletinized starch are sieved through a 500 micron sieve and blended in a suitable mixer.
  • the magnesium starate is sieved through a 250 micron sieve and blended with the active blend.
  • the blend is compressed into tablets using suitable punches, then coated with cellulose acetate phthalate in a conventional manner.

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Claims (10)

  1. Pharmazeutische Formulierung in fester Arzneiform zur oralen Verabreichung, die eine Verbindung der Formel (I)
    Figure 00160001
       und physiologische Salze und Solvate davon umfasst, worin:
    X entweder Wasserstoff, Trifluormethyl, Alkyl, C1-4-Alkylthio, -O(C1-4-Alkyl) oder Halogen ist;
    R1 entweder Formel (II) oder -NR4R5 ist;
    Figure 00160002
    R2 entweder:
    (1) ein an seiner 2-Position gebundener Heterocyclus, der aus Pyrrol, Tetrahydropyrrol, Indol, Benzofuran, Thiophen, Benzothiophen, Indolin, Chinolin oder 4-Oxobenzopyran ausgewählt ist und worin das Pyrrol, Tetrahydropyrrol, Indol oder Indolin gegebenenfalls am Ringstickstoff davon mit der Gruppe R8 wie nachfolgend definiert substituiert sein kann und das Indol, Indolin, Chinolin, Benzofuran, Benzothiophen oder 4-Oxobenzopyran gegebenenfalls im Benzoring davon mit der Gruppe R9 wie nachfolgend definiert substituiert sein kann; oder
    (2) Phenyl oder unabhängig mit Halogen, Hydroxy, Cyano, Carboxy, - (C1-4-Alkyl), -O(CH2C6H5), -COO(C1-4-Alkyl), Amino, Dimethylamino, -NHR10, 1-Pyrrolidinyl oder Tetrazolyl mono- oder disubstituiertes Phenyl; oder
    (3) Pyridin oder unabhängig mit Halogen, Methyl, Hydroxy, Nitro, Cyano, Carboxy, -O(C1-4-Alkyl), -O(CH2C6H5), -COO(C1-4-Alkyl), Amino oder Dimethylamino mono- oder disubstituiertes Pyridinyl; oder
    (4) -NHR11 ist, worin R11 wie nachfolgend definiert ist oder R11 7-Indazolyl ist, das eine Gruppe R10 an der N-1-Position enthält;
    R3 Wasserstoff, C1-6-Alkyl, C3-6-Cycloalkyl, Phenyl oder unabhängig mit Halogen mono- oder disubstituiertes Phenyl ist;
    R4 unabhängig C3-6-Alkyl, C3-6-Cycloalkyl, C3-6-Alkenyl, Phenyl, -(CH2)pCN oder -(CH2)pCOO(C1-4-Alkyl) ist und R5 unabhängig C3-6-alkyl, C3-6-Cycloalkyl, C3-6-Alkenyl, Benzyl, Phenyl oder unabhängig mit C1-3-Alkyl, Cyano, Hydroxy, Dimethylamino, -O(C1-4-Alkyl), -O(CH2C6H5), -NH(C1-4-Alkyl), -COO(C1-4-Alkyl), -N(C1-4-Alkyl)2, Pyrrolidino, Morpholino oder Halogen mono- oder disubstituiertes Phenyl ist oder R4 C1-2-Alkyl ist und R5 in der 2- oder 4-Position mit Chlor, Methyl, Methoxy oder Methoxycarbonyl substituiertes Phenyl ist;
    R6 Wasserstoff oder Methyl ist;
    R7 Wasserstoff, Hydroxy, Fluor, Dimethylamino, -O(C1-4-Alkyl) oder -O(CH2C6H5) ist;
    R8 -(CH2)bCOOH ist;
    R9 Methyl, Chlor, Nitro, Hydroxy, Methoxy oder -NHR10 ist;
    R10 Wasserstoff, Acetyl, C1-4-Alkyl, -SO3H, -SO2CH3, -SO2CF3 oder -SO2C6H5, C1-4-Alkoxycarbonyl ist;
    R11 Phenyl oder unabhängig mit Fluor, Trifluormethoxy, C1-4-Alkylthio, -(CH2)cCOOH, -(CH2)cCOO(C1-4-Alkyl), -(CH2)cSCH3, -(CH2)cSOCH3, -(CH2)cSO2CH3, -(CH2)cCONH2, -SCH2COOH, -CONH(SO2CH3), -CONH(SO2CF3), -(CH2)cN(C1-4-Alkyl)2, -(CH2)cNH(SO2CF3), -(CH2)cN(SO2CF3)(C1-4-Alkyl), -(CH2)cSO2NHCO(C1-4-Alkyl), -(CH2)cSO2N(C1-4-Alkyl)CO(C1-4-alkyl), -(CH2)cCONHSO2(C1-4-Alkyl), -(CH2)cCON(C1-4-Alkyl)SO2(C1-4-alkyl), -(CH2)cOR12, -(CH2)cNHR10 mono- oder disubstituiertes Phenyl oder mit -(CH2)c(Tetrazolyl), -(CH2)c(Carboxamidotetrazolyl) oder -(CH2)c(Pyrrolidinyl) monosubstituiertes Phenyl ist oder R11 aus Pyridin oder unabhängig mit Halogen, Methyl, Hydroxy, Nitro, Cyano, Carboxy, - O(C1-4-Alkyl), Amino, Dimethylamino, -NHR10 mono- oder disubstituiertem Pyridinyl ausgewählt ist;
    R12 Wasserstoff, C1-6-Alkyl, C3-6-Cycloalkyl, -CH2C6H5, -CH2COOH, -CH2CONH2, -CH2CONH(C1-4-Alkyl), -CH2CON(C1-4-Alkyl)2 oder
    Figure 00180001
    ist;
    z 1 oder 2 ist;
    n 1 oder 2 ist;
    p eine ganze Zahl von 1 bis 4 ist;
    b eine ganze Zahl von 0 bis 3 ist; und
    c 0 oder 1 ist,
       zusammen mit einem oder mehreren pharmazeutisch akzeptablen Trägern, worin die Formulierung in einem magensaftresistenten Überzug oder einer magensaftresistenten Kapsel verkapselt ist.
  2. Pharmazeutische Zusammensetzung gemäss Anspruch 1, worin R1 die Gruppe der Formel (II) darstellt, worin R6 Methyl ist, R7 Wasserstoff, Hydroxyl, Methoxy oder Fluor ist und n 1 ist, oder R1 die Gruppe NR4R5 darstellt, worin R4 C3-6-Alkyl, Cyclohexyl oder Phenyl darstellt, und R5 C3-6-Alkyl oder Phenyl darstellt, das gegebenenfalls in der para-Position mit Hydroxy, Dimethylamino, Methoxy, Fluor, Pyrrolidino oder Morpholino substituiert ist.
  3. Pharmazeutische Zusammensetzung gemäss Anspruch 1 oder 2, worin R1 die Gruppe NR4R5 darstellt und R4 Propyl oder Isopropyl darstellt und R5 Phenyl oder in der para-Position mit einer Gruppe substituiertes Phenyl darstellt, die aus Hydroxy, Methoxy, Dimethylamino, Fluor oder Morpholino ausgewählt ist.
  4. Pharmazeutische Zusammensetzung gemäss einem der Ansprüche 1 bis 3, worin R2 eine Gruppe darstellt, ausgewählt aus Phenyl (gegebenenfalls substituiert mit einer oder zwei Gruppen, die gleich oder verschieden sein können und ausgewählt sind aus Chlor, Fluor, Amino, Hydroxy oder Carboxy) oder NHR11, worin R11 Phenyl (gegebenenfalls substituiert mit Fluor, Hydroxy, Amino, Dimethylamino, Trifluormethylsulfonylamino, C1-4-Alkoxycarbonyl, Carboxy, 1H-Tetrazol-5-yl, Acetylamino oder OR12 ist, worin R12 Wasserstoff, Methyl, Benzyl, CH2CO2H, CH2CONH2, CH2CONHCH3, CH2CON(CH3)2
    Figure 00180002
       ist) oder 7-Indazolyl ist, worin der N-1-Substituent R10 Wasserstoff ist oder R2 eine Indolgruppe darstellt, worin das Stickstoffatom gegebenenfalls mit der Gruppe -CH2CO2H substituiert ist und der Benzoring gegebenenfalls mit einer Gruppe substituiert ist, die aus Chlor, Methyl, Methoxy, Nitro, Hydroxy oder Amino ausgewählt ist.
  5. Pharmazeutische Zusammensetzung gemäss einem der Ansprüche 1 bis 4, worin R2 eine Indolgruppe darstellt, die am Stickstoffatom unsubstituiert ist und worin der Benzoring davon gegebenenfalls mit einer Gruppe substituiert ist, die aus Chlor, Methyl, Methoxy, Nitro, Hydroxy oder Amino ausgewählt ist.
  6. Pharmazeutische Zusammensetzung gemäss einem der Ansprüche 1 bis 5, worin R3 Wasserstoff, Methyl, Cyclohexyl, 2-Fluorphenyl oder Phenyl darstellt.
  7. Pharmazeutische Zusammensetzung gemäss einem der Ansprüche 1 bis 6, worin R3 Phenyl darstellt.
  8. Pharmazeutische Zusammensetzung gemäss einem der Ansprüche 1 bis 7, worin X Wasserstoff darstellt.
  9. Pharmazeutische Zusammensetzung gemäss Anspruch 1, worin R1 NR4R5 darstellt und R4 Isopropyl darstellt und R5 p-Methoxyphenyl darstellt; R2 eine unsubstituierte 2-Indolgruppe darstellt; R3 Phenyl darstellt und X Wasserstoff darstellt und Enantiomere davon.
  10. Pharmazeutische Zusammensetzung gemäss Anspruch 1 in Form einer magensaftresistent überzogenen Tablette.
EP95935725A 1994-10-14 1995-10-13 Zubereitungen von 1,5-benzodiazepinderivaten mit cck-antagonistischen oder agonistischer wirkung mit enterischem überzug Expired - Lifetime EP0785794B1 (de)

Priority Applications (1)

Application Number Priority Date Filing Date Title
SI9530576T SI0785794T1 (en) 1994-10-14 1995-10-13 Enteric coated compositions of 1,5-benzodiazepine derivatives having cck antagonistic or agonistic activity

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
GB9420748A GB9420748D0 (en) 1994-10-14 1994-10-14 1,5 benzodiazepine derivatives
GB9420748 1994-10-14
PCT/US1995/012829 WO1996011701A1 (en) 1994-10-14 1995-10-13 Enteric coated compositions of 1,5-benzodiazepine derivatives having cck antagonistic or agonistic activity

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EP0785794A1 EP0785794A1 (de) 1997-07-30
EP0785794B1 true EP0785794B1 (de) 2001-12-19

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EP (1) EP0785794B1 (de)
JP (1) JP3907700B2 (de)
AT (1) ATE210986T1 (de)
AU (1) AU3763495A (de)
DE (1) DE69524781T2 (de)
DK (1) DK0785794T3 (de)
ES (1) ES2170168T3 (de)
GB (1) GB9420748D0 (de)
PT (1) PT785794E (de)
SI (1) SI0785794T1 (de)
WO (1) WO1996011701A1 (de)

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US6558952B1 (en) * 1992-12-14 2003-05-06 Waratah Pharmaceuticals, Inc. Treatment for diabetes
JP4530433B2 (ja) * 1996-05-07 2010-08-25 プリヴァ・ディー・ディー 脂質及びグルコースの代謝疾患治療のための方法及び組成物
CN118994191A (zh) 2016-02-05 2024-11-22 戴纳立制药公司 受体相互作用蛋白激酶1的抑制剂
HRP20220636T1 (hr) 2016-12-09 2022-07-22 Denali Therapeutics Inc. Spojevi korisni kao inhibitori ripk1
AU2023206890A1 (en) 2022-01-12 2024-08-22 Denali Therapeutics Inc. Crystalline forms of (s)-5-benzyl-n-(5-methyl-4-oxo-2, 3,4,5- tetrahydropyrido [3,2-b] [l,4]oxazepin-3-yl)-4h-l,2,4-triazole-3-carboxamide

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GR890100827A (el) * 1988-12-21 1991-03-15 Abbott Lab Μέ?οδος παραγωγής παραγώγων τετραπεπτιδίων ως ανταγωνιστών CCK.
GB9201180D0 (en) * 1992-01-21 1992-03-11 Glaxo Group Ltd Chemical compounds
GB9307833D0 (en) * 1993-04-15 1993-06-02 Glaxo Inc Modulators of cholecystokinin and gastrin

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Publication number Publication date
SI0785794T1 (en) 2002-08-31
DE69524781D1 (de) 2002-01-31
JP3907700B2 (ja) 2007-04-18
JPH10511930A (ja) 1998-11-17
PT785794E (pt) 2002-06-28
DE69524781T2 (de) 2002-06-20
ES2170168T3 (es) 2002-08-01
AU3763495A (en) 1996-05-06
WO1996011701A1 (en) 1996-04-25
GB9420748D0 (en) 1994-11-30
DK0785794T3 (da) 2002-03-18
ATE210986T1 (de) 2002-01-15
EP0785794A1 (de) 1997-07-30

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